The overall goal of my research is to understand the mechanisms by which the activation of cortical inhibitory and excitatory circuits by incoming sensory information is modulated. The central hypothesis of this proposal is that presynaptic GABAB, adenosinc, and metabotropic glutamate receptors modulate thalamocortical stimulation of cortical inhibition. It is becoming increasingly clear that cortical inhibitory circuits play very important roles in sensory processing and cortical reorganization. Therefore, understanding how the activation of these inhibitory cortical circuits is regulated will provide important insights into how sensory processing can be altered pharmacologically. Perhaps in the future one would have the ability to alter sensory processing via receptor agonists or antagonists in order to assist in new skill learning, relearning after an accident or stroke, or treatment of conditions like phantom limb pain which have aberrant cortical reorganization. However, before any such interventions can be done we need more detailed information on the types and subtypes of receptors that regulate the activation of inhibitory cortical circuits via incoming sensory information. To begin to address; this deficit in our knowledge and extend the initial observations found during the first three years of this grant, the following aims are proposed. Specific Aim 1: To test the hypothesis that metabotropic glutamate receptors modulate thalamocortical excitation of inhibitory neurons. Specific Aim 2: To test the hypothesis that endogenously released GABA, adenosine. and glutamate can modulate thalamocortical excitation of inhibitory neurons. Specific Aim 3: To test the hypothesis that presynaptic GABAn, adenosine A1 and metabotropic glutamate receptors modulate thalamocortical stimulation in adult animals. Specific Aim 4: To test the hypothesis that intracortical and thalamocortical synapses are differentially reg,ulated by GABAB, adenosine and metabotropic glutamate receptors. Detailed knowledge of the pharmacology and physiology of the mechanisms which regulate the thalamic activation of cortical inhibitory circuits could improve treatments for people recovering from strokes or accidents.